The primary objective of this project is to continue our development and application of new approaches to the surgical management of cutaneous melanoma. During the last grant period, lymphatic mapping and sentinel lymphadenectomy (LM/SLND) was prospectively examined as a staging alternative to complete lymphadenectomy in patients with clinical stage I melanoma. This Multicenter Selective Lymphadenectomy Trial (MSLT-I) has completed accrual of 2001 patients, who are now being followed to determine whether there is a survival benefit of complete lymph node dissection (CLND) for patients who have histopathological evidence of sentinel node (SN) micrometastases. Because most patients with SN micrometastases have no other tumor-involved nodes, CLND may not be necessary. We will investigate this hypothesis in a new multicenter randomized trial (MSLT-II). This trial will introduce lymphatic injection of carbon dye to confirm the identity of the SN and to pinpoint the area of this node that drains the primary melanoma, for focused pathological exam. Specimens from both MSLT trials will be used to develop and assess new immunologic markers, molecular markers (with 0003), and pathologic markers relating to the SN's tumor burden, architecture, and microenvironment (with 0005). These markers should enable us to determine the likelihood of metastasis beyond the SN and thereby identify candidates for CLND and adjuvant therapy. In related phase II trials, we will examine the phenomenon of SN immunosuppression as a predisposing factor for establishment of nodal metastasis, and the possibility of reversing this immunosuppression by cytokine therapy. 1. Continue a multicenter trial of intraoperative LM/SLND for the management of clinical stage I melanoma (MSLT-1). 2. Begin a multicenter trial to determine whether LM/SLND and CLND is superior to LM/SLND alone in patients with evidence of metastases in the SNs by histopathological or molecular techniques (MSLT-II). 3. Test the hypothesis that new immunologic and molecular tumor markers can be used to identify subclinical (micrometastatic) melanoma and identify those patients who are at high risk of recurrence after surgical therapy. 4. Examine the interaction between tumor burden and endogenous immune response as a determinant of the clinical outcome in melanoma. 5. Determine whether certain morphological changes that indicate immune downregulation of the SN can predict nonsentinel and systemic metastases, and whether these morphological changes are reversible with cytokine therapy.